Hepatocellular carcinoma (HCC) is the fastest rising cause of cancer related deaths in the United States. Survival is dismal except in a relatively small number of cases that are detected early and subjected to potentially curative treatment. Therefore, periodic surveillance for HCC has been recommended in patients with liver cirrhosis. Serum alpha-fetoprotein (AFP) has been extensively used as a marker for HCC detection, but its performance in the surveillance for HCC has been generally low. However, AFP test characteristics are influenced by severity and activity of liver disease that are partly reflected n serum levels of AST, ALT, bilirubin, platelets, etc. Incorporating some of these factors into an adjusted AFP-based algorithm may improve its predictive value in detecting HCC. Our preliminary predictive logistic model with AFP, age, ALT, and total bilirubin as continuous non-linear variables and interaction terms (AFP*ALT, AFP*bilirubin) found marked improvement in predicting HCC occurrence in the 6 months following an AFP test compared to AFP alone. This work has been accepted for publication in Gastroenterology. The proposed study will optimize the predictive utility of this promising yet preliminary algorithm by using an updated derivation dataset with longer follow up and more HCC cases, validate and refine the algorithm in two independent cohorts of HCV- and non HCV- related cirrhosis patients from the Department of Veterans Affairs (VA) and Kaiser Permanente Northern California (KPNC), and evaluate its clinical utility in detecting early HCC in comparison to liver ultrasound- and AFP -based screening at KPNC. Aim 1 (DERIVATION OF THE ADJUSTED AFP ALGORITHM): To maximize the predictive value of our preliminary AFP based model (adjusted AFP) in predicting the occurrence of HCC and estimate cutoffs for positive or abnormal results in a large derivation dataset of patients with cirrhosis and hepatitis C infection. Aim 2 (EXTERNAL VALIDATION): To test the use of our adjusted AFP model in predicting the risk of HCC in two external cohorts of patients with cirrhosis due to various etiologies. Aim 3 (TESTING OF CLINICAL UTILITY): To examine the clinical utility of the adjusted AFP algorithm in improving early HCC detection compared to standard serum AFP test with or without liver ultrasound screening (US) test. Given the wide availability of AFP tests, their high level of lab standardization, low cost, and the absence of promising and readily available new biomarkers, we believe that an adjusted AFP based algorithm may have an immediate utility and impact on clinical practice.